EP0725627A1 - Orally-administered dosage form for animals, preparation method therefor and uses thereof - Google Patents

Orally-administered dosage form for animals, preparation method therefor and uses thereof

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Publication number
EP0725627A1
EP0725627A1 EP95900166A EP95900166A EP0725627A1 EP 0725627 A1 EP0725627 A1 EP 0725627A1 EP 95900166 A EP95900166 A EP 95900166A EP 95900166 A EP95900166 A EP 95900166A EP 0725627 A1 EP0725627 A1 EP 0725627A1
Authority
EP
European Patent Office
Prior art keywords
substances
form according
outer layer
chosen
substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP95900166A
Other languages
German (de)
French (fr)
Other versions
EP0725627B1 (en
Inventor
Guy Derrieu
André Aubert
Bernard Raynier
Carolin L. Schumacher
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Virbac SA
Original Assignee
Laboratoires Virbac SA
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Publication date
Application filed by Laboratoires Virbac SA filed Critical Laboratoires Virbac SA
Publication of EP0725627A1 publication Critical patent/EP0725627A1/en
Application granted granted Critical
Publication of EP0725627B1 publication Critical patent/EP0725627B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating

Definitions

  • the present invention relates to a dosage form intended to allow the oral administration of chemical or medicinal substances, such as vitamins, trace elements, amino acids, nutritional substances, vaccines, etc., to animals. domestic or wild.
  • chemical or medicinal substances such as vitamins, trace elements, amino acids, nutritional substances, vaccines, etc.
  • the present invention also relates to the process for obtaining said dosage forms.
  • Patent EP 0 240 826 Patent EP 0 208 528 and Patent Application EP 0 421 863.
  • the bait described in Patent EP 0 240 826 is obtained by a first casting, at the bottom of a mold, of a support comprising a lipid compound (having a melting point between 20 ° and 60 ° C), a compound intended to stabilize the shape of the bait and an attractive and appetizing compound for animals, placing the active substance on the solidified support layer, then a second casting of said support, so as to completely cover said active substance.
  • a lipid compound having a melting point between 20 ° and 60 ° C
  • This system has the disadvantage of having low mechanical strength and fragility in the vicinity of the junction of the two flows and makes it unsuitable for large-scale distribution methods (air drop, for example, for treating large numbers of wild animals , on important territories).
  • Patent EP 208 528 describes a bait for fish and crustaceans consisting essentially of a polymer insoluble in water having a melting point lower than 110 ° C. (polyamides or copolymers of ylene, EVA, in particular), an attractive substance and edible oil or molasses (0 to 20%).
  • the baits according to this Patent EP 208 528 are obtained by extrusion at 90-110 ° C. from a dry mixture of the polymer, the attractive substance and optionally edible oil.
  • compositions according to this PCT International Application WO 89/12393 can be in the form of blocks or tablets and are also prepared by extrusion of the abovementioned composition, either by melting of the polymer (fusible at a temperature ⁇ 110 ° C.) , followed by mixing the latter with the other ingredients, either by heating, to the melting point of the polymer, with a mixture of all the ingredients in dry form.
  • Patent Application EP 421 863 describes systems comprising two parts: a casing in tubular form, obtained by extrusion and comprising at least one attractive substance, at least one agglomerating substance (polysaccharides, starches or polymers such as EVA) and optionally a substance hydrophobic (oil) and inside the envelope cavity, a bonding substance (mixture of fatty substances having a low melting point) containing an active principle, the bonding substance taking on the internal form of the envelope.
  • a casing in tubular form obtained by extrusion and comprising at least one attractive substance, at least one agglomerating substance (polysaccharides, starches or polymers such as EVA) and optionally a substance hydrophobic (oil) and inside the envelope cavity, a bonding substance (mixture of fatty substances having a low melting point) containing an active principle, the bonding substance taking on the internal form of the envelope.
  • agglomerating substance polysaccharides, starches or polymers such as EVA
  • compositions or systems of the prior art are generally designed in such a way that they exhibit good resistance to handling and to shock and / or good attractiveness towards animals, facilitating the effective uptake of the active ingredient (s) included in these systems.
  • compositions described in these documents do not provide the active principles with a residence time in the oral cavity sufficient to guarantee the effectiveness of certain drugs or when it is essential to obtain a certain time contact, especially for certain treatments.
  • active ingredients do not provide the active ingredients with satisfactory stability, in particular those of biological origin.
  • Application EP 458 751 describes a system comprising a central core comprising cyclic amino acids, a first coating composed of a polymer capable of forming a film (5% -100% of the core by weight) and a second hydrophobic coating consisting of lipids (20% - 400% by weight of the core + first coating combination) allowing granules to be obtained, essentially intended to be subjected to another transformation; in addition, such systems induce a controlled release of the active principle and do not make it possible to transform and stabilize products of biological origin in aqueous solution or suspension.
  • the present invention has, therefore, given itself the aim of providing a new dosage form which better meets the requirements encountered in the treatment of certain ailments, in the provision of certain treatments, in the execution of certain edict acts. waters on animals, such as for example oral vaccination or treatments of the oral cavity, as the compositions and systems of the prior art.
  • the subject of the present invention is a pharmaceutical form for the oral administration of chemical or medicinal substances, of the type comprising a solid central core containing one or more biological substances. active and an outer layer or coating, characterized in that:
  • the central, water-soluble and porous core includes:. at least one substance chosen from the group which comprises the binders selected from poly ⁇ peptides, high molecular weight polysaccharides, polymers which can give colloidal solutions and colloids, and the diluents selected from polyols, metal oxides ⁇ lics, carbonates, phosphates or microcrystalline cellulose, the overall amount of binder and diluent being between 50 and 98% by weight relative to said central core and.
  • an effective amount of at least one bioactive substance and the outer layer, hydrophobic and palatable comprises: at least one lipid substance chosen from fatty alcohols (cetyl alcohol, stearyl alcohol), fatty acids (stearic acid, palmitic acid), glycerol esters such as glycerol palmitostearate, glyce ⁇ rol stearate (marketed under the brand PRECIROL), glycerol behenate (marketed under the brand COMPRITOL), hydrogenated oils such as oil hydrogenated castor (sold under the brand CUTINA HR), waxes or fatty substances such as carnauba wax, beeswax, paraffin, lanolin, coconut oil and the fatty acid salts such as calcium or stearate magnesium; .
  • fatty alcohols cetyl alcohol, stearyl alcohol
  • fatty acids stearic acid, palmitic acid
  • glycerol esters such as glycerol palmitostearate, glyce ⁇ rol stea
  • an agent for modulating the disintegration of said outer layer and the adhesion of the microparticulate fragments resulting from the disintegration of the central nucleus, soluble or dispersible in the lipid mass chosen from selected polymers in the group which includes acrylic resins (sold under the brand EUDRAGIT), polyvinyl acetates (sold under the brand RHODOPAS), polyalkylene resins, ethylene / vinyl acetate (EVA) copolymers, poly ⁇ crosslinked mothers of starch, dextran, inulin or vinylpyrrolidone and cellulose derivatives selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, carboxymethylcellulose; and
  • palatable substances natural or synthetic, of purely vegetable origin or containing products of animal origin, chosen from meat or fish meal, aromas such as boiled beef aroma, roasted pork aroma, white fish aroma, peanut flavor, bacon flavor, liver flavor.
  • This dosage form is therefore double compartment.
  • the first compartment at its core, is a central core, solid and porous, having the characteristics of dissolving or disintegrating quickly in an aqueous medium or in saliva.
  • the microparticulate aggregates or fragments generated by this disintegration are liable to adhere to the tissues of the oral cavity, due to the particular composition of the form according to the invention.
  • the second compartment is in fact a pel ⁇ licule or envelope of both lipid and polymeric nature, hydrophobic, palatable and of controlled thickness which ensures:
  • active ingredient is understood to mean any biologically active material and more especially any molecule which may present formulation difficulties linked to problems of taste, poor solubility or insolubility, instability, or low bioavailability.
  • the dosage form according to the invention can be used for the administration of all kinds of substances, commonly used in veterinary medicine and more particularly to oral vaccines, nutrition agents, metabolism regulating agents, contraceptives, extracts of plants, food additives, hygiene and dietetic agents, cosmetic agents.
  • This new form also allows a solid presentation of active liquid ingredients.
  • active substances which can be administered in this form the following can be cited:
  • antibiotics such as betalactamines (amoxicillin, ampicillin, cefalexin), chloramphenicol, macrolides (josamycin, erythromycin, spiramycin, tylosin), tetracyclines,
  • antibiotics such as furans, quinolones, sulfonamides, sulfones, trimethemury,
  • - anti-inflammatory drugs such as corticoids, pyrazoles, salicylates, non-steroids,
  • anthelmintics such as oxibendazole, pyrantel, mebendazole, oxfendazole, fenbendazole, netobimin,
  • - nutritional agents such as oral rehydrating agents, amino acids (methionine, lysine), mineral or vitamin energy supply products,
  • Peptides Nucleic acid compounds Composed of biological molecules associated with various cytokines: IL2, IL6, IL12, interferon; TNF ...
  • Antisense nucleosides are antisense nucleosides. .Anti-idiotypic monoclonal antibodies or not Specific cell receptors
  • TH1 specific immunity cellular immunity
  • TH2 salivary-derived TH1 specific immunity
  • binder is understood to mean a thickening and structuring substance serving as a support, soluble or dispersible in water, making it possible to ensure the cohesion of the mass, inert with respect to the active principle (s). ) and capable of promoting the adhesion of the microparticulate fragments of the central nucleus to the mucous membranes of the oral cavity, after the actual dosage form has been taken by the animal.
  • binders are in particular chosen from polypeptides such as gelatin or partially hydrolyzed gelatin, polysaccharides with high molecular weight, polymers which can give colloidal solutions and colloids, such as natural or synthetic gums, (gum arabic, caraya gum, xanthan gum, guar gum, locust bean gum), alginates, cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, pectinates, car- rageenanes, dextrans, homo or copolymers of acrylic acid, water-dispersible derivatives of starch, colloidal silicas, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycols (PEG 6000 and 8000 in particular), or alternatively mixtures of said binders.
  • polypeptides such as gelatin or partially hydrolyzed gelatin, polysaccharides with high molecular weight, polymers which can give colloidal solutions and colloids, such as natural or synthetic gums, (gum
  • these binders are more particularly chosen from gum arabic, xanthan gum, pectin, natural biopolymers commonly used in the preparation of tablets or chewing gum to improve bioadhesion to the mucous membranes of the cavity buccal.
  • diuent denotes pharmaceutically acceptable substances, preferably water-soluble substances, which improve the physical properties of the central nucleus. These substances can in particular be chosen from mannitol, xylitol, lactose, glycine, sorbitol, glucose, maltodextrins, cyclodextrins, or also from oxides (magnesium oxide), carbonates (calcium carbonate), phosphates (tricalcium phosphate), microcrystalline cellulose.
  • the central core further comprises one or more additives chosen from substances modifying or masking the taste such as sac ⁇ charine, saccharinates, cyclamates, aspartame, agents modulating disintegration such as silica, absorption promoters such as cyclodextrins or salts of glycyrrhetinic acid, surface agents chosen from nonionic or cationic surfactants, such as sorbitan esters, co ⁇ polymers of ethylene and propylene oxide, polyoxyethylene and fatty alcohol ethers, coloring agents and preservatives.
  • additives chosen from substances modifying or masking the taste such as sac ⁇ charine, saccharinates, cyclamates, aspartame, agents modulating disintegration such as silica, absorption promoters such as cyclodextrins or salts of glycyrrhetinic acid, surface agents chosen from nonionic or cationic surfactants, such as sorbitan esters, co ⁇ polymers of
  • the central core therefore contains at least one substance chosen from the binders and diluents listed above, but it can contain one or more binders and / or one or more diluents.
  • the lipid substance of said outer layer is chosen from paraffin, coconut oil, palmitic acid and glycerol esters and the agent for modulating the disintegration of said outer layer is chosen from ethylene / vinyl acetate copolymers and crosslinked polysaccharides.
  • the hydrophobic outer layer or barrier of the dosage form according to the invention may also contain:
  • mineral substances chosen from the group which comprises the mineral oxides selected from titanium and iron oxide, phosphates, carbonates, clays and talc, which substances also act on the disintegration speed of said outer layer and /or
  • a surfactant chosen, for example, from sorbitol esters, polyoxyethylene polysorbates (sold under the brand TWEEN), lecithins, sorbitan esters, to guarantee the homogeneity and the transformation of the mixture. killing, when it is in the form of a suspension during the coating operation (coating) of the central core.
  • This hydrophobic material may advantageously contain esters of glycerol and of fatty acids, such as mono and / or diglycerides, the major impact of which will be to increase the affinity between the lipid layer and the central nucleus, thus promoting the adhesion between the two compartments of the dosage form according to the invention. Flexibility and elasticity relative of the film-forming material are reinforced.
  • said galenic form advantageously comprises: - central core: diluents and / or binders 50 to 98% bioactive substances 0.25 to 50% other additives 0 to 1.75%
  • the present invention also relates to a process for the preparation of the dosage form in accordance with the invention, characterized in that the following operations are carried out: a) preparation of a paste containing the various constituents of the central core, namely , bioactive substances, diluents, binders and possibly one or more additives and a quantity of water suitable for adjusting the homogeneity and viscosity of the suspension obtained, b) solidification of the product obtained in a), c ) coating of the products obtained in b), with a mixture in solution or in suspension, comprising at least one lipid substance, an agent for modulating the disintegration of the outer layer and a palatable substance.
  • the preparation of the central core takes place according to the following operations: a) preparation of a paste containing the various constituents listed above, as well as a suitable quantity of water so as to provide the suspension obtained with rheological characteristics allowing optimal transformation; b) solidification of the product obtained in a), in particular by freezing and sublimation (lyophilization) in particular when the active principle is a vac ⁇ cin, or equivalent operation.
  • said solidification is carried out by a physical operation such as evaporation, drying or lyophilization.
  • the paste obtained in a) is preferably divided into unit quantities of shape and volume determined before freezing and sublimation.
  • the active principle (s) will be soluble or in suspension in the paste to be distributed, in free form or in the form of microparticles or nanoparticles.
  • This latter form which is more particularly suitable for solidification by freeze-drying, can avoid the complete and immediate release of the active principle when it is brought into contact with aqueous media and the salivary flow.
  • Bio-absorbable polymers or macromolecular substances are used in the constitution of micro or nanoparticles.
  • the coating of the central core described above is carried out according to the usual techniques commonly used in the pharmaceutical and food industry. Depending on the shape and the size of the central core, the solvent evaporation coating, the coacervation coating, the coating by turbine coating, the coating in a fluidized air bed or the dip coating widely used in the food industry, more specifically confectionery.
  • the dosage form according to the invention is particularly indicated:
  • buccal bio-adhesion formulations such as, for example, breath freshening systems
  • the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention.
  • EXAMPLE I Unit form for dental hygiene.
  • a premix is prepared containing the active principles and excipients and having the following composition: 0.25% chlorhexidine diacetate
  • the pulverulent mass is mixed dry for 30 minutes then added with water, at a rate of 38 g per 100 g of dry mass, and kneaded for 1 hour at room temperature.
  • the homogeneous suspension thus obtained is divided into 1.5 cm 3 polyvinyl chloride cells.
  • the blister sheet containing the suspension is introduced into a lyophilizer immediately after division, to be frozen at a temperature of -45 ° C under atmospheric pressure, for approximately 3 hours. After drying for 12 hours under reduced pressure at a negative temperature, the temperature rises to 30 ° C in steps of 5 ° C.
  • the freeze-dried unit, extracted from the cell, is treated in an air bed fluidized (GLATT GPC-15) with air injection (100 liters / min, at 30-5 ° C), with a solution of hydrogenated cas ⁇ tor oil (1 part), ethyl cellulose (2.5 parts), beeswax (3 parts), cetyl alcohol (1 part), peanut flavor (0.15 parts) in methylene chloride (80 parts), maintained at 25- 30 ° C.
  • Example II A stability study of the dosage form according to Example II was carried out by following the title of the vaccine suspension, as a function of the time and the temperature of storage. This study was conducted in parallel with a control batch of vaccine suspension, stored in liquid form and packaged in a blister. The controls are carried out within 7, 14 and 28 days, 3 and 6 months following the preparation of the suspension and the corresponding dosage form. The weekly drop in the infectious cyto-pathogenic dose destroying 50% of the cells (DICP50) is expressed on the two preparations. The results are collated in Table I and show the particular advantage of the dosage form compared to a conventional presentation.
  • the 14 dogs rete- naked are divided into 4 groups A, B, C and D.
  • Group A (4 dogs) receives the dosage form according to the invention
  • group B (4 dogs) receives the lyophilized central nucleus (without the protective compartment)
  • group C (4 dogs) receives a conventional bait
  • group D (2 dogs) is not treated.
  • the dogs are followed for 30 days, by monitoring the development of the level of rabies antibodies. At 30 days, the seroconversion rates are greater than 0.5 IU for 4, 3 and 3 dogs, respectively in groups A, B and C.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Polymers & Plastics (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Food Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Feed For Specific Animals (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

PCT No. PCT/FR94/01251 Sec. 371 Date Aug. 1, 1996 Sec. 102(e) Date Aug. 1, 1996 PCT Filed Oct. 27, 1994 PCT Pub. No. WO95/11665 PCT Pub. Date May 4, 1995A dosage form for orally administering chemical or medicinal substances such as vitamins, trace elements, amino acids, nutritive substances, vaccines, etc., to domestic or wild animals, and a method for preparing same, are disclosed. Said dosage form includes: a porous water-soluble central core containing binders selected from polypeptides, polysaccharides, polymers and colloids, and/or diluents selected from polyols, metal oxides, carbonates, phosphates and microcrystalline cellulose, and an effective amount of at least one bioactive substance; and a palatable hydrophobic outer layer containing at least one lipid substance selected from fatty alcohols, fatty acids, glycerol esters, hydrogenated oils, waxes, paraffin, lanolin, coconut oil and fatty acid salts; a polymeric agent for modulating the disintegration and adhesion of said outer layer, and natural or synthetic palatable substances.

Description

FORME GALENIQUE A ADMINISTRATION ORALE POUR ANIMAUX, SON PROCEDE DE PREPARATION ET SES APPLICATIONS. GALENIC FORM WITH ORAL ADMINISTRATION FOR ANIMALS, PREPARATION METHOD THEREOF AND APPLICATIONS THEREOF.
La présente invention est relative à une forme galénique destinée à permettre l'administration orale de substances chimiques ou médicamenteuses, telles que vita¬ mines, oligo-éléments, amino-acides, substances nutri- tionnelles, vaccins etc..., à des animaux domestiques ou sauvages .The present invention relates to a dosage form intended to allow the oral administration of chemical or medicinal substances, such as vitamins, trace elements, amino acids, nutritional substances, vaccines, etc., to animals. domestic or wild.
La présente invention est également relative au procédé d'obtention desdites formes galéniques.The present invention also relates to the process for obtaining said dosage forms.
On connaît déjà des systèmes permettant l'administration orale de médicaments à des animaux do¬ mestiques ou à des animaux élevés de manière extensive, ou à des animaux sauvages, difficiles ou dangereux à contenir.Systems are already known for the oral administration of medicaments to domestic animals or to animals reared extensively, or to wild animals, difficult or dangerous to contain.
De tels systèmes ont fait l'objet de Demandes de Brevet ou de Brevets (Brevet EP 0 240 826, Brevet EP 0 208 528 et Demande de Brevet EP 0 421 863) .Such systems have been the subject of Patent Applications or Patents (Patent EP 0 240 826, Patent EP 0 208 528 and Patent Application EP 0 421 863).
L'appât décrit dans le Brevet EP 0 240 826 est obtenu par une première coulée, au fond d'un moule, d'un support comprenant un composé lipidique (ayant un point de fusion entre 20° et 60°C), un composé destiné à stabi¬ liser la forme de l'appât et un composé attractif et ap- pétant pour les animaux, une mise en place de la sub- stance active sur la couche de support solidifiée, puis une deuxième coulée dudit support, de manière à recouvrir complètement ladite substance active.The bait described in Patent EP 0 240 826 is obtained by a first casting, at the bottom of a mold, of a support comprising a lipid compound (having a melting point between 20 ° and 60 ° C), a compound intended to stabilize the shape of the bait and an attractive and appetizing compound for animals, placing the active substance on the solidified support layer, then a second casting of said support, so as to completely cover said active substance.
Ce système a 1 ' inconvénient de présenter une faible résistance mécanique et une fragilité au voisinage de la jonction des deux coulées et le rend inapte aux modes de distribution à grande échelle (largage aérien, par exemple, pour traiter des effectifs importants d'animaux sauvages, sur des territoires importants) .This system has the disadvantage of having low mechanical strength and fragility in the vicinity of the junction of the two flows and makes it unsuitable for large-scale distribution methods (air drop, for example, for treating large numbers of wild animals , on important territories).
Le Brevet EP 208 528 décrit un appât pour poissons et crustacés constitué essentiellement d'un po¬ lymère insoluble dans l'eau ayant un point de fusion in¬ férieur à 110 °C (polyamides ou copolymères d'ét ylène, EVA, en particulier) , d'une substance attractive et d'huile comestible ou de mélasse (0 à 20 %) .Patent EP 208 528 describes a bait for fish and crustaceans consisting essentially of a polymer insoluble in water having a melting point lower than 110 ° C. (polyamides or copolymers of ylene, EVA, in particular), an attractive substance and edible oil or molasses (0 to 20%).
Les appâts selon ce Brevet EP 208 528 sont ob¬ tenus par extrusion à 90-110 'C d'un mélange à sec du po- lymère, de la substance attractive et éventuellement de l'huile comestible.The baits according to this Patent EP 208 528 are obtained by extrusion at 90-110 ° C. from a dry mixture of the polymer, the attractive substance and optionally edible oil.
La Demande Internationale WO 89/12393 décrit des compositions pesticides comprenant de l'EVA, un agent bioactif, une source de protéines/sucres/lipides et éven- tuellement 0 à 20 % d'huile comestible, une substance at¬ tractive, un colorant, un conservateur, un agent répulsif et un biomarqueur.International Application WO 89/12393 describes pesticidal compositions comprising EVA, a bioactive agent, a source of proteins / sugars / lipids and possibly 0 to 20% edible oil, an attractive substance, a colorant , a preservative, a repellant and a biomarker.
Les compositions selon cette Demande Inter¬ nationale PCT WO 89/12393 peuvent être sous forme de blocs ou de comprimés et sont également préparées par ex¬ trusion de la composition précitée, soit par fusion du polymère (fusible à une température < 110 °C), suivie du mélange de ce dernier avec les autres ingrédients, soit par chauffage, jusqu'au point de fusion du polymère, d'un mélange de l'ensemble des ingrédients sous forme sèche.The compositions according to this PCT International Application WO 89/12393 can be in the form of blocks or tablets and are also prepared by extrusion of the abovementioned composition, either by melting of the polymer (fusible at a temperature <110 ° C.) , followed by mixing the latter with the other ingredients, either by heating, to the melting point of the polymer, with a mixture of all the ingredients in dry form.
La Demande de Brevet EP 421 863 décrit des systèmes comprenant deux parties : une enveloppe sous forme tubulaire, obtenue par extrusion et comprenant au moins une substance attractive, au moins une substance agglomérante (polyosides, amidons ou polymères tels que EVA) et éventuellement une substance hydrophobe (huile) et à l'intérieur de la cavité de l'enveloppe, une sub¬ stance de liaison (mélange de corps gras possédant un point de fusion peu élevé) contenant un principe actif, la substance de liaison épousant la forme interne de l'enveloppe. Une telle enveloppe possède une résistance mécanique et thermique élevée, permettant notamment la distribution par largage aérien.Patent Application EP 421 863 describes systems comprising two parts: a casing in tubular form, obtained by extrusion and comprising at least one attractive substance, at least one agglomerating substance (polysaccharides, starches or polymers such as EVA) and optionally a substance hydrophobic (oil) and inside the envelope cavity, a bonding substance (mixture of fatty substances having a low melting point) containing an active principle, the bonding substance taking on the internal form of the envelope. Such an envelope has a high mechanical and thermal resistance, allowing in particular the distribution by air release.
Les compositions ou systèmes de l'Art anté- rieur sont généralement conçus de telle façon qu'ils pré¬ sentent une bonne résistance à la manipulation et aux chocs et/ou une bonne attractivité vis-à-vis des animaux, facilitant la prise effective du (ou des) principe (s) actif (s) inclus dans ces systèmes.The compositions or systems of the prior art are generally designed in such a way that they exhibit good resistance to handling and to shock and / or good attractiveness towards animals, facilitating the effective uptake of the active ingredient (s) included in these systems.
Toutefois, de façon générale, les compositions décrites dans ces documents n'assurent pas aux principes actifs un temps de séjour dans la cavité buccale suffi¬ sant pour garantir l'efficacité de certains médicaments ou lorsqu'il est indispensable d'obtenir un certain temps de contact, notamment pour certains traitements. De plus, elles n'assurent pas aux principes actifs une stabilité satisfaisante, en particulier à ceux d'origine biolo¬ gique.However, in general, the compositions described in these documents do not provide the active principles with a residence time in the oral cavity sufficient to guarantee the effectiveness of certain drugs or when it is essential to obtain a certain time contact, especially for certain treatments. In addition, they do not provide the active ingredients with satisfactory stability, in particular those of biological origin.
La Demande EP 458 751 décrit un système com¬ prenant un noyau central comprenant des aminoacides cy- cliques, un premier enrobage composé d'un polymère apte à former un film (5 %-100 % du noyau en poids) et un deuxième enrobage hydrophobe consistant en lipides (20 %- 400 % en poids de la combinaison noyau+ premier enrobage) permettant l'obtention de granules, essentiellement des- tinés à être soumis à une autre transformation ; en outre, de tels systèmes induisent une libération contrô¬ lée du principe actif et ne permettent pas de transformer et de stabiliser des produits d'origine biologique en solution ou suspension aqueuse. La présente invention s'est, en conséquence, donné pour but de fournir une nouvelle forme galénique qui répond mieux aux exigences rencontrées dans le trai¬ tement de certaines affections, dans la dispensation de certains soins, dans l'exécution de certains actes édi- eaux sur les animaux, tels que par exemple la vaccination orale ou les traitements de la cavité buccale, que les compositions et systèmes de l'Art antérieur.Application EP 458 751 describes a system comprising a central core comprising cyclic amino acids, a first coating composed of a polymer capable of forming a film (5% -100% of the core by weight) and a second hydrophobic coating consisting of lipids (20% - 400% by weight of the core + first coating combination) allowing granules to be obtained, essentially intended to be subjected to another transformation; in addition, such systems induce a controlled release of the active principle and do not make it possible to transform and stabilize products of biological origin in aqueous solution or suspension. The present invention has, therefore, given itself the aim of providing a new dosage form which better meets the requirements encountered in the treatment of certain ailments, in the provision of certain treatments, in the execution of certain edict acts. waters on animals, such as for example oral vaccination or treatments of the oral cavity, as the compositions and systems of the prior art.
La présente invention a pour objet une forme galénique pour l'administration orale de substances chi- miques ou médicamenteuses, du type comprenant un noyau central solide contenant une ou plusieurs substances bio- actives et une couche externe ou enrobage, caractérisée en ce que :The subject of the present invention is a pharmaceutical form for the oral administration of chemical or medicinal substances, of the type comprising a solid central core containing one or more biological substances. active and an outer layer or coating, characterized in that:
- le noyau central, hydrosoluble, et poreux com¬ prend : . au moins une substance choisie dans le groupe qui comprend les liants sélectionnés parmi des poly¬ peptides, des polysaccharides à poids moléculaire élevé, des polymères pouvant donner des solutions colloïdales et des colloïdes, et les diluants sé- lectionnés parmi des polyols, des oxydes métal¬ liques, des carbonates, des phosphates ou la cellu¬ lose microcristalline, la quantité globale de liant et de diluant étant comprise entre 50 et 98 % en poids par rapport audit noyau central et . une quantité efficace d'au moins une substance bioactive et la couche externe, à caractère hydrophobe et appétant, comprend : au moins une substance lipidique choisie parmi les alcools gras (alcool cétylique, alcool stéary- lique) , les acides gras (acide stéarique, acide palmitique) , les esters de glycerol tels que le palmitostéarate de glycerol, le stéarate de glyce¬ rol (commercialisé sous la marque PRECIROL) , le béhénate de glycerol (commercialisé sous la marque COMPRITOL) , les huiles hydrogénées telles que l'huile de ricin hydrogénée (commercialisée sous la marque CUTINA HR) , les cires ou corps gras tels que cire de carnauba, cire d'abeille, paraffine, lano- line, huile de coprah et les sels d'acides gras tels que stéarate de calcium ou de magnésium ; . un agent de modulation du délitement de ladite couche externe et de l'adhésion des fragments microparticulaires issus de la désintégration du noyau central, soluble ou dispersible dans la masse lipidique, choisi parmi des polymères sélectionnés dans le groupe qui comprend des résines acryliques (commercialisées sous la marque EUDRAGIT) , des acé¬ tates de polyvinyle (commercialisés sous la marque RHODOPAS) , des résines de polyalkylène, des copoly- mères éthylène/acétate de vinyle (EVA) , les poly¬ mères réticulés d'amidon, de dextran, d'inuline ou de vinylpyrrolidone et des dérivés cellulosiques sélectionnés parmi 1 'hydroxypropylcellulose, 1 'hydroxypropylméthylcellulose, 1 'éthylcellulose, la carboxyméthylcellulose ; et- the central, water-soluble and porous core includes:. at least one substance chosen from the group which comprises the binders selected from poly¬ peptides, high molecular weight polysaccharides, polymers which can give colloidal solutions and colloids, and the diluents selected from polyols, metal oxides ¬ lics, carbonates, phosphates or microcrystalline cellulose, the overall amount of binder and diluent being between 50 and 98% by weight relative to said central core and. an effective amount of at least one bioactive substance and the outer layer, hydrophobic and palatable, comprises: at least one lipid substance chosen from fatty alcohols (cetyl alcohol, stearyl alcohol), fatty acids (stearic acid, palmitic acid), glycerol esters such as glycerol palmitostearate, glyce¬ rol stearate (marketed under the brand PRECIROL), glycerol behenate (marketed under the brand COMPRITOL), hydrogenated oils such as oil hydrogenated castor (sold under the brand CUTINA HR), waxes or fatty substances such as carnauba wax, beeswax, paraffin, lanolin, coconut oil and the fatty acid salts such as calcium or stearate magnesium; . an agent for modulating the disintegration of said outer layer and the adhesion of the microparticulate fragments resulting from the disintegration of the central nucleus, soluble or dispersible in the lipid mass, chosen from selected polymers in the group which includes acrylic resins (sold under the brand EUDRAGIT), polyvinyl acetates (sold under the brand RHODOPAS), polyalkylene resins, ethylene / vinyl acetate (EVA) copolymers, poly ¬ crosslinked mothers of starch, dextran, inulin or vinylpyrrolidone and cellulose derivatives selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, carboxymethylcellulose; and
. des substances appétentes, naturelles ou synthé¬ tiques, d'origine purement végétale ou contenant des produits d'origine animale, choisies parmi les farines de viande ou de poisson, les arômes tels que arôme boeuf bouilli, arôme porc rôti, arôme poisson blanc, arôme arachide, arôme bacon, arôme foie.. palatable substances, natural or synthetic, of purely vegetable origin or containing products of animal origin, chosen from meat or fish meal, aromas such as boiled beef aroma, roasted pork aroma, white fish aroma, peanut flavor, bacon flavor, liver flavor.
Cette forme galénique est donc à double com¬ partiment. Le premier compartiment, à coeur, est un noyau central, solide et poreux, ayant pour caractéristiques de se dissoudre ou de se désintégrer rapidement en milieu aqueux ou dans la salive. Les agrégats ou fragments microparticulaires générés par cette désintégration sont susceptibles d'adhérer aux tissus de la cavité buccale, en raison de la composition particulière de la forme se¬ lon l'invention.This dosage form is therefore double compartment. The first compartment, at its core, is a central core, solid and porous, having the characteristics of dissolving or disintegrating quickly in an aqueous medium or in saliva. The microparticulate aggregates or fragments generated by this disintegration are liable to adhere to the tissues of the oral cavity, due to the particular composition of the form according to the invention.
Le deuxième compartiment est en fait une pel¬ licule ou enveloppe de nature à la fois lipidique et polymérique, hydrophobe, appétente et d'épaisseur contrô- lée qui assure :The second compartment is in fact a pel¬ licule or envelope of both lipid and polymeric nature, hydrophobic, palatable and of controlled thickness which ensures:
- une manipulation aisée de la forme galénique selon l'invention, sans modifier l'intégrité du compartiment central, hydrosoluble et de structure poreuse,- easy handling of the dosage form according to the invention, without modifying the integrity of the central compartment, water-soluble and of porous structure,
- une protection du noyau central contre l'humidité, - une protection contre la contamination de la personne chargée de dispenser le produit, en particulier pour la vaccination orale,- protection of the central core against humidity, - protection against contamination by the person responsible for dispensing the product, in particular for oral vaccination,
- une attractivité vis-à-vis de l'animal cible, - une bonne résistance thermique à des températures com¬ prises entre -30° C et +45° C, sans modification de la texture, ni suintement lipidique,- attractiveness towards the target animal, - good thermal resistance at temperatures between -30 ° C and + 45 ° C, without modification of the texture or lipid oozing,
- une stabilité optimale du noyau central solide et sec, et donc des molécules bioactives sensibles, - une stabilité dans le temps, les caractéristiques phy¬ siques étant non altérables, lors du séjour dans le milieu de distribution, plus particulièrement pour les animaux d'élevage intensif, et- optimal stability of the solid and dry central nucleus, and therefore of the sensitive bioactive molecules, - stability over time, the physical characteristics being non-alterable during the stay in the distribution medium, more particularly for animals of intensive farming, and
- une bioadhésion aux muqueuses de la cavité buccale et une mise à disposition immédiate des principes actifs aux travers de celles-ci, ce qui conduit à une bio¬ disponibilité optimale, alors que les comprimés ou autres appâts selon l'Art antérieur, ont un contenu trop compact ou trop fluide pour permettre une persis- tance dans la cavité buccale.- Bioadhesion to the mucous membranes of the oral cavity and immediate availability of the active ingredients through them, which leads to optimal bio¬ availability, whereas the tablets or other baits according to the prior art have a contents too compact or too fluid to allow persistence in the oral cavity.
On entend par principe actif toute matière biologiquement active et plus spécialement toute molécule pouvant présenter des difficultés de formulation liées à des problèmes de goût, de faible solubilité ou d'insolubilité, d'instabilité, ou à une biodisponibilité faible.The term active ingredient is understood to mean any biologically active material and more especially any molecule which may present formulation difficulties linked to problems of taste, poor solubility or insolubility, instability, or low bioavailability.
La forme galénique selon 1 ' invention peut être utilisée pour l'administration de toutes sortes de sub¬ stances, communément utilisées en médecine vétérinaire et plus particulièrement aux vaccins oraux, aux agents de nutrition, aux agents régulateurs des métabolismes, aux contraceptifs, aux extraits de plantes, aux adjuvants d'alimentation, aux agents d'hygiène et de diététique, aux agents cosmétiques. Cette nouvelle forme permet, en outre, une présentation solide de principes actifs li¬ quides. A titre d'exemple, parmi les substances ac¬ tives administrables sous cette forme, peuvent être ci¬ tés :The dosage form according to the invention can be used for the administration of all kinds of substances, commonly used in veterinary medicine and more particularly to oral vaccines, nutrition agents, metabolism regulating agents, contraceptives, extracts of plants, food additives, hygiene and dietetic agents, cosmetic agents. This new form also allows a solid presentation of active liquid ingredients. By way of example, among the active substances which can be administered in this form, the following can be cited:
- les antibiotiques tels que betalactamines (amoxicilline, ampicilline, cefalexine) , chloramphéni- col, macrolides (josamycine, érythromycine, spira- mycine, tylosine) , tétracyclines,- antibiotics such as betalactamines (amoxicillin, ampicillin, cefalexin), chloramphenicol, macrolides (josamycin, erythromycin, spiramycin, tylosin), tetracyclines,
- les antiinfectieux autres que antibiotiques tels que furanes, quinolones, sulfamides, sulfones, trimétho- prime,- anti-infectives other than antibiotics such as furans, quinolones, sulfonamides, sulfones, trimethemury,
- les antiinflammatoires tels que corticoïdes, pyra- zoles, salicylés, non stéroidiens,- anti-inflammatory drugs such as corticoids, pyrazoles, salicylates, non-steroids,
- les antimycosiques tels que griséofulvine, kétonazole,- antimycotics such as griseofulvin, ketonazole,
- les anthelminthiques tels que oxibendazole, pyrantel, mébendazole, oxfendazole, fenbendazole, netobimin,- anthelmintics such as oxibendazole, pyrantel, mebendazole, oxfendazole, fenbendazole, netobimin,
- les agents de nutrition, tels que réhydratants oraux, acides aminés (méthionine, lysine) produits d'apports énergétiques minéraux ou vitaminiques,- nutritional agents, such as oral rehydrating agents, amino acids (methionine, lysine), mineral or vitamin energy supply products,
- les produits locaux gingivodentaires, antiseptiques, antibactériens, tels que hexamidine, chlorhexidine, hexitidine, et les substances modifiant l'haleine,- local gingivodentary, antiseptic, antibacterial products, such as hexamidine, chlorhexidine, hexitidine, and breath-modifying substances,
- les vaccins anti-viraux, anti-bactériens, anti-parasi¬ taires, sous forme : . Inactivés : antigène complet Vivants atténués Vivants mutés avirulents- anti-viral, anti-bacterial, anti-parasitic vaccines, in the form:. Inactivated: complete antigen Attenuated living Mutant avirulent living
Vivant issus de recombinaison génétique (vecteur viraux, bactériens, plasmidiques) . Sous unitaires : (glycoprotéine ; nucléoprotéine) Recombinants purifiés : molécules antigéniques puresLive from genetic recombination (viral, bacterial, plasmid vectors). Subunits: (glycoprotein; nucleoprotein) Purified recombinants: pure antigenic molecules
Peptidiques Composés d'acide nucléiques Composés de molécules biologiques associées à diverses cytokines : IL2 , IL6, IL12 , interféron ; TNF ...Peptides Nucleic acid compounds Composed of biological molecules associated with various cytokines: IL2, IL6, IL12, interferon; TNF ...
Nucléosides anti-sens . .Anticorps monoclonaux anti-idiotypiques ou pas Récepteurs cellulaires spécifiquesAntisense nucleosides. .Anti-idiotypic monoclonal antibodies or not Specific cell receptors
- les cytokines,- cytokines,
- les anti-cancéreux,- anti-cancer drugs,
- les facteurs de croissances, - les vaccins contraceptifs hormonaux ou pas,- growth factors, - hormonal contraceptive vaccines or not,
- les insecticides biologiques,- biological insecticides,
- les adjuvants non spécifiques de 1 ' immunité spécifiques de THl (immunité cellulaire) . spécifiques de TH2 (immunité humorale) .- non-specific adjuvants of TH1 specific immunity (cellular immunity). specific for TH2 (humoral immunity).
- les facteurs, support de transgénie,- factors, support for transgenics,
- les facteurs d'attachement ou anti-attachement locaux (muqueuses, villosités intestinales ... ) .- local attachment or anti-attachment factors (mucous membranes, intestinal villi, etc.).
On entend par liant une substance épaissis- santé et structurante servant de support, soluble ou dispersible dans l'eau, permettant d'assurer la cohésion de la masse, inerte vis-à-vis du (des) principe (s) actif (s) et susceptible de favoriser l'adhésion des frag¬ ments microparticulaires du noyau central aux muqueuses de la cavité buccale, après la prise effective de ladite forme galénique par 1 ' animal.The term “binder” is understood to mean a thickening and structuring substance serving as a support, soluble or dispersible in water, making it possible to ensure the cohesion of the mass, inert with respect to the active principle (s). ) and capable of promoting the adhesion of the microparticulate fragments of the central nucleus to the mucous membranes of the oral cavity, after the actual dosage form has been taken by the animal.
Ces liants sont notamment choisis parmi les polypeptides tels que la gélatine ou la gélatine partiel¬ lement hydrolysée, des polysaccharides à poids molécu- laire élevé, des polymères pouvant donner des solutions colloïdales et des colloïdes, tels que les gommes natu¬ relles ou synthétiques, (la gomme arabique, la gomme caraya, la gomme xanthane, la gomme guar, la gomme de caroube), les alginates, les dérivés cellulosiques tels que la carboxyméthyl cellulose sodique, 1 'hydroxypropylméthyl cellulose, les pectinates, les car- rageenanes, les dextranes, les homo ou copolymères de l'acide acrylique, les dérivés hydrodispersibles de l'amidon, les silices colloïdales, l'alcool polyviny- lique, la polyvinylpyrrolidone, les polyéthylèneglycols (PEG 6000 et 8000 particulièrement) , ou encore des mélanges desdits liants.These binders are in particular chosen from polypeptides such as gelatin or partially hydrolyzed gelatin, polysaccharides with high molecular weight, polymers which can give colloidal solutions and colloids, such as natural or synthetic gums, (gum arabic, caraya gum, xanthan gum, guar gum, locust bean gum), alginates, cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, pectinates, car- rageenanes, dextrans, homo or copolymers of acrylic acid, water-dispersible derivatives of starch, colloidal silicas, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycols (PEG 6000 and 8000 in particular), or alternatively mixtures of said binders.
De manière avantageuse, ces liants sont plus particulièrement choisis parmi la gomme arabique, la gomme xanthane, la pectine, biopolymères naturels com u- nément utilisés dans l'élaboration des comprimés ou gommes à mâcher pour améliorer la bioadhésion aux mu¬ queuses de la cavité buccale.Advantageously, these binders are more particularly chosen from gum arabic, xanthan gum, pectin, natural biopolymers commonly used in the preparation of tablets or chewing gum to improve bioadhesion to the mucous membranes of the cavity buccal.
On désigne par diluant des substances pharmaceutiquement acceptables, de préférence hydro- solubles, qui améliorent les propriétés physiques du noyau central. Ces substances peuvent être notamment choisies parmi le mannitol, le xylitol, le lactose, le glycocolle, le sorbitol, le glucose, les maltodextrines, les cyclodextrines, ou encore parmi les oxydes (oxyde de magnésium) , les carbonates (carbonate de calcium) , les phosphates (phosphate tricalcique) , la cellulose microcristalline.The term “diluent” denotes pharmaceutically acceptable substances, preferably water-soluble substances, which improve the physical properties of the central nucleus. These substances can in particular be chosen from mannitol, xylitol, lactose, glycine, sorbitol, glucose, maltodextrins, cyclodextrins, or also from oxides (magnesium oxide), carbonates (calcium carbonate), phosphates (tricalcium phosphate), microcrystalline cellulose.
Selon un mode de réalisation avantageux de ladite forme galénique, le noyau central comprend en outre un ou plusieurs additifs choisis parmi des sub¬ stances modifiant ou masquant le goût telles que la sac¬ charine, les saccharinates, les cyclamates, l'aspartame, des agents modulant le délitement comme la silice, des promoteurs d'absorption tels que les cyclodextrines ou les sels de l'acide glycyrrhétinique, des agents de sur¬ face choisis parmi des tensio-actifs non ioniques ou cationiques, tels que les esters de sorbitane, les co¬ polymères d'oxyde d'éthylène et de propylène, les éthers de polyoxyéthylène et d'alcool gras, des agents colorants et des agents conservateurs. Le noyau central contient donc au moins une substance choisie parmi les liants et diluants énumérés ci-dessus, mais il peut contenir un ou plusieurs liants et/ou un ou plusieurs diluants. Selon un autre mode de réalisation avantageux de ladite forme galénique, la substance lipidique de ladite couche externe est choisie parmi la paraffine, l'huile de coprah, l'acide palmitique et les esters du glycerol et l'agent de modulation du délitement de ladite couche externe est choisi parmi les copolymères éthylène/acétate de vinyle et les polysaccharides réticu¬ lés.According to an advantageous embodiment of said dosage form, the central core further comprises one or more additives chosen from substances modifying or masking the taste such as sac¬ charine, saccharinates, cyclamates, aspartame, agents modulating disintegration such as silica, absorption promoters such as cyclodextrins or salts of glycyrrhetinic acid, surface agents chosen from nonionic or cationic surfactants, such as sorbitan esters, co¬ polymers of ethylene and propylene oxide, polyoxyethylene and fatty alcohol ethers, coloring agents and preservatives. The central core therefore contains at least one substance chosen from the binders and diluents listed above, but it can contain one or more binders and / or one or more diluents. According to another advantageous embodiment of said dosage form, the lipid substance of said outer layer is chosen from paraffin, coconut oil, palmitic acid and glycerol esters and the agent for modulating the disintegration of said outer layer is chosen from ethylene / vinyl acetate copolymers and crosslinked polysaccharides.
Conformément à l'invention, la couche externe ou barrière hydrophobe de la forme galénique selon 1 ' invention pourra également contenir :According to the invention, the hydrophobic outer layer or barrier of the dosage form according to the invention may also contain:
- des substances minérales choisies dans le groupe qui comprend les oxydes minéraux sélectionnés parmi l'oxyde de titane et de fer, les phosphates, les carbonates, les argiles et le talc, lesquelles substances agissent également sur la vitesse de délitement de ladite couche externe et/ou- mineral substances chosen from the group which comprises the mineral oxides selected from titanium and iron oxide, phosphates, carbonates, clays and talc, which substances also act on the disintegration speed of said outer layer and /or
- un agent tensio-actif choisi par exemple parmi les esters de sorbitol, les polysorbates de poly- oxyéthylène (commercialisés sous la marque TWEEN) , les lécithines, les esters de sorbitane, pour garantir l'homogénéité et la transformation du mélange la consti¬ tuant, lorsque celle-ci se présente sous la forme d'une suspension lors de l'opération de pelliculage (d'enrobage) du noyau central. Cette matière hydrophobe pourra avantageusement contenir des esters du glycerol et d'acides gras, tels que mono et (ou) diglycérides, dont l'incidence majeure sera d'accroître l'affinité entre la couche lipidique et le noyau central, favorisant ainsi l'adhésion entre les deux compartiments de la forme galé- nique selon l'invention. La flexibilité et l'élasticité relative de la matière filmogène s ' en trouvent renfor¬ cées .a surfactant chosen, for example, from sorbitol esters, polyoxyethylene polysorbates (sold under the brand TWEEN), lecithins, sorbitan esters, to guarantee the homogeneity and the transformation of the mixture. killing, when it is in the form of a suspension during the coating operation (coating) of the central core. This hydrophobic material may advantageously contain esters of glycerol and of fatty acids, such as mono and / or diglycerides, the major impact of which will be to increase the affinity between the lipid layer and the central nucleus, thus promoting the adhesion between the two compartments of the dosage form according to the invention. Flexibility and elasticity relative of the film-forming material are reinforced.
Conformément à l'invention, ladite forme galé¬ nique comprend avantageusement : - noyau central : diluants et/ou liants 50 à 98 % substances bioactives 0,25 à 50 % autres additifs 0 à 1,75 %According to the invention, said galenic form advantageously comprises: - central core: diluents and / or binders 50 to 98% bioactive substances 0.25 to 50% other additives 0 to 1.75%
- couche externe : substances lipidiques 40 à 93 % polymères 4 à 30 % substances appétentes et autres additifs 3 à 30 %- outer layer: lipid substances 40 to 93% polymers 4 to 30% palatable substances and other additives 3 to 30%
La présente invention a également pour objet un procédé de préparation de la forme galénique conforme à l'invention, caractérisé en ce que l'on effectue les opérations suivantes : a) préparation d'une pâte contenant les différents constituants du noyau central, à savoir, sub- stances bioactives, diluants, liants et éven¬ tuellement un ou plusieurs additifs et une quan¬ tité d'eau convenable pour régler l'homogénéité et la viscosité de la suspension obtenue, b) solidification du produit obtenu en a) , c) enrobage des produits obtenus en b) , avec un mélange en solution ou en suspension, comprenant au moins une substance lipidique, un agent de modulation du délitement de la couche externe et une substance appétente. De manière plus précise, la préparation du noyau central se déroule selon les opérations suivantes : a) préparation d'une pâte contenant les différents constituants énumérés plus avant, ainsi qu'une quantité d'eau convenable de manière à assurer à la suspension obtenue des caractéristiques rhéo- logiques permettant une transformation optimale ; b) solidification du produit obtenu en a) , notamment par congélation et sublimation (lyophilisation) en particulier lorsque le principe actif est un vac¬ cin, ou opération équivalente. Selon un mode de mise en oeuvre avantageux dudit procédé, ladite solidification est réalisée par une opération physique telle qu' evaporation, dessiccation ou lyophilisation.The present invention also relates to a process for the preparation of the dosage form in accordance with the invention, characterized in that the following operations are carried out: a) preparation of a paste containing the various constituents of the central core, namely , bioactive substances, diluents, binders and possibly one or more additives and a quantity of water suitable for adjusting the homogeneity and viscosity of the suspension obtained, b) solidification of the product obtained in a), c ) coating of the products obtained in b), with a mixture in solution or in suspension, comprising at least one lipid substance, an agent for modulating the disintegration of the outer layer and a palatable substance. More specifically, the preparation of the central core takes place according to the following operations: a) preparation of a paste containing the various constituents listed above, as well as a suitable quantity of water so as to provide the suspension obtained with rheological characteristics allowing optimal transformation; b) solidification of the product obtained in a), in particular by freezing and sublimation (lyophilization) in particular when the active principle is a vac¬ cin, or equivalent operation. According to an advantageous embodiment of said method, said solidification is carried out by a physical operation such as evaporation, drying or lyophilization.
Lorsque la solidification est réalisée par evaporation, celle-ci est réalisée sous pression réduite et de préférence associée à une exposition aux hyper- fréquences. Cette transformation, réalisée par exemple dans un mélangeur sécheur VRIECO-NAUTA ou VACTRON (MACHINES COLETTE), sera préférée lorsqu'on souhaitera obtenir une unité de forme sphérique ou globalement sphé- rique, les conditions d'utilisation permettant de moduler la taille moyenne du noyau central selon l'invention.When solidification is carried out by evaporation, this is carried out under reduced pressure and preferably associated with exposure to microwave frequencies. This transformation, carried out for example in a VRIECO-NAUTA or VACTRON mixer mixer (COLETTE MACHINES), will be preferred when it is desired to obtain a unit of spherical or globally spherical shape, the conditions of use making it possible to modulate the average size of the central core according to the invention.
Lorsque la solidification est réalisée par lyophilisation, la pâte obtenue en a) est de préférence divisée en quantités unitaires de forme et de volume déterminés avant congélation et sublimation.When the solidification is carried out by lyophilization, the paste obtained in a) is preferably divided into unit quantities of shape and volume determined before freezing and sublimation.
Il est entendu que la division du produit peut également être effectuée mécaniquement après lyophilisa¬ tion, mais il est avantageux de répartir la pâte dans des alvéoles de forme et de dimensions prédéterminées, préalablement à l'opération de lyophilisation.It is understood that the division of the product can also be carried out mechanically after lyophilization, but it is advantageous to distribute the dough in cells of predetermined shape and size, prior to the lyophilization operation.
Conformément à l'invention, le(s) principe (s) actif (s) seront solubles ou en suspension dans la pâte à répartir, sous forme libre ou sous forme de microparti- cules ou nanoparticules. Cette dernière forme, plus par¬ ticulièrement adaptée à une solidification par lyophili¬ sation, peut éviter le relargage complet et immédiat du principe actif lors de la mise en contact avec les milieux aqueux et le flux salivaire. Des polymères bio- résorbables ou des substances macromoléculaires entrent dans la constitution des micro ou nanoparticules . L'enrobage du noyau central précédemment décrit est effectuée selon les techniques usuelles commu¬ nément employées dans l'industrie pharmaceutique et ali¬ mentaire. Selon la forme et la dimension du noyau cen- tral, on utilisera plus particulièrement l'enrobage par evaporation du solvant, l'enrobage par coacervation, l'enrobage par pelliculage en turbine, l'enrobage en lit d'air fluidisé ou l'enrobage par trempage largement em¬ ployé dans l'industrie alimentaire, plus précisément la confiserie.In accordance with the invention, the active principle (s) will be soluble or in suspension in the paste to be distributed, in free form or in the form of microparticles or nanoparticles. This latter form, which is more particularly suitable for solidification by freeze-drying, can avoid the complete and immediate release of the active principle when it is brought into contact with aqueous media and the salivary flow. Bio-absorbable polymers or macromolecular substances are used in the constitution of micro or nanoparticles. The coating of the central core described above is carried out according to the usual techniques commonly used in the pharmaceutical and food industry. Depending on the shape and the size of the central core, the solvent evaporation coating, the coacervation coating, the coating by turbine coating, the coating in a fluidized air bed or the dip coating widely used in the food industry, more specifically confectionery.
La forme galénique conforme à 1 ' invention est tout particulièrement indiquée :The dosage form according to the invention is particularly indicated:
- pour les formulations pharmaceutiques orales dont il convient de masquer le goût des substances bioac- tives,- for oral pharmaceutical formulations, the taste of bioactive substances for which should be masked,
- pour les formulations à bio-adhésion buc¬ cale, comme par exemple les systèmes de rafraîchissement de l'haleine,- for buccal bio-adhesion formulations, such as, for example, breath freshening systems,
- pour les formulations incluant des principes actifs sensibles aux mécanismes de la digestion et dont on stimulera le passage par les muqueuses de la cavité buccale.- for formulations including active ingredients sensitive to the mechanisms of digestion and which will stimulate the passage through the mucous membranes of the oral cavity.
Outre les dispositions qui précèdent, l'invention comprend encore d'autres dispositions, qui ressortiront de la description qui va suivre, qui se réfère à des exemples de mise en oeuvre du procédé objet de la présente invention.In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention.
Il doit être bien entendu, toutefois, que ces exemples sont donnés uniquement à titre d'illustration de l'objet de l'invention, dont ils ne constituent en aucune manière une limitation.It should be understood, however, that these examples are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation.
EXEMPLE I : Forme unitaire pour l'hygiène dentaire.EXAMPLE I: Unit form for dental hygiene.
Dans un mélangeur planétaire de type OLSA, on prépare un pré-mélange contenant les principes actifs et excipients et ayant la composition suivante : Chlorhexidine diacétate 0,25 %In a planetary mixer of the OLSA type, a premix is prepared containing the active principles and excipients and having the following composition: 0.25% chlorhexidine diacetate
Méthionine 3 %Methionine 3%
Lactose 80 % β-cyclodextrine 13 % Dextran 70 2 %Lactose 80% β-cyclodextrin 13% Dextran 70 2%
Silice pulvérisée 0,25 %0.25% sprayed silica
Aspartame 0,8 %Aspartame 0.8%
Monopalmitate de sorbitane 0,7 %Sorbitan monopalmitate 0.7%
La masse pulvérulente est mélangée à sec pen- dant 30 minutes puis additionnée d'eau, à raison de 38 g pour 100 g de masse sèche, et malaxée pendant 1 heure à température ambiante. La suspension homogène ainsi obte¬ nue est divisée dans des alvéoles de chlorure de poly- vinyle de 1,5 cm3. La feuille alvéolée contenant la sus- pension est introduite dans un lyophilisateur immédiate¬ ment après division, pour être congelée à une température de -45° C sous pression atmosphérique, pendant environ 3 heures. Après dessiccation pendant 12 heures sous pres¬ sion réduite à une température négative, la température est remontée à 30° C par paliers de 5° C. L'unité lyophi¬ lisée, extraite de l'alvéole, est traitée en lit d'air fluidisé (GLATT GPC-15) avec injection d'air (100 litres/min, à 30-5° C) , par une solution d'huile de cas¬ tor hydrogénée (1 partie), d'éthyl cellulose (2,5 par- ties) , de cire d'abeille (3 parties), d'alcool cétylique (1 partie), d'arôme arachide (0,15 partie) dans le chlo¬ rure de méthylène (80 parties), maintenu à 25-30°C. EXEMPLE II : Forme unitaire pour la vaccination orale contre la rage chez le chien. En opérant comme décrit précédemment pour l'exemple I, on engage un mélange sec ayant la composi¬ tion suivante :The pulverulent mass is mixed dry for 30 minutes then added with water, at a rate of 38 g per 100 g of dry mass, and kneaded for 1 hour at room temperature. The homogeneous suspension thus obtained is divided into 1.5 cm 3 polyvinyl chloride cells. The blister sheet containing the suspension is introduced into a lyophilizer immediately after division, to be frozen at a temperature of -45 ° C under atmospheric pressure, for approximately 3 hours. After drying for 12 hours under reduced pressure at a negative temperature, the temperature rises to 30 ° C in steps of 5 ° C. The freeze-dried unit, extracted from the cell, is treated in an air bed fluidized (GLATT GPC-15) with air injection (100 liters / min, at 30-5 ° C), with a solution of hydrogenated cas¬ tor oil (1 part), ethyl cellulose (2.5 parts), beeswax (3 parts), cetyl alcohol (1 part), peanut flavor (0.15 parts) in methylene chloride (80 parts), maintained at 25- 30 ° C. EXAMPLE II Unit form for oral vaccination against rabies in dogs. By operating as described above for Example I, a dry mixture having the following composition is used:
Lactose 28 %Lactose 28%
Mannitol 70 % Gomme arabique 2 % On additionne une suspension vaccinale de souche SAG-2 de titre suffisant pour garantir 1 ' immunité à l'animal vacciné, à raison de 40 g pour 100 g de masse sèche et on opère comme décrit plus haut. L'unité lyophilisée, extraite de l'alvéole, est enrobée par trempage, dans un mélange homogène maintenu à 56-60° C, de composition suivante : Paraffine 50-2° C (52 %) , co- polymère éthylène acétate de vinyle à 28 % d'acétate de vinyle (6 %) , farine de viande (23 %) , suif de boeuf (17 %) , arôme bacon de ROBERTET (2 %) . On obtient ainsi une forme galénique selon 1 ' invention propre à la vacci¬ nation orale. EXEMPLE III :Mannitol 70% Gum arabic 2% A vaccine suspension of strain SAG-2 is added of sufficient strength to guarantee immunity to the vaccinated animal, at a rate of 40 g per 100 g of dry mass and the procedure is as described above. The lyophilized unit, extracted from the cell, is coated by soaking, in a homogeneous mixture maintained at 56-60 ° C, of the following composition: Paraffin 50-2 ° C (52%), ethylene vinyl acetate copolymer 28% vinyl acetate (6%), meat meal (23%), beef tallow (17%), ROBERTET bacon flavor (2%). A galenical form according to the invention specific to oral vacci¬ nation is thus obtained. EXAMPLE III:
Dans un mélangeur sécheur planétaire pouvant supporter une pression réduite et équipé d'un générateur d'hyperfréquences, on réalise un mélange ayant la compo¬ sition suivante :In a planetary mixer-dryer capable of withstanding reduced pressure and equipped with a microwave generator, a mixture is produced having the following composition:
Lactose 20 %Lactose 20%
Mannitol 45 % Polyvinyl pyrrolidone K 30 6 %Mannitol 45% Polyvinyl pyrrolidone K 30 6%
Phosphate bicalcique 5 %Bicalcium phosphate 5%
Sulfaméthoxypyridazine 20 %Sulfamethoxypyridazine 20%
Triméthoprime 4 %Trimethoprim 4%
Eau 45 g pour 100 g de masse sècheWater 45 g per 100 g dry mass
On mélange pendant 1 heure, puis on effectue l'élimination de l'eau sous vide à l'aide de micro-ondes (excitation en discontinu avec des générateurs de puis¬ sance variable entre 1 et 4 KW) , en ne dépassant pas 40°C. Les granules obtenus sont enrobés en lit d'air fluidisé par une pulvérisation d'une solution à 5 % d'Eudragit® L 100, contenant une faible quantité de mono- glyceride d'acide gras et d'anhydride silicique anhydre, dans un mélange 1/1 de chlorure de méthylène et d' isopropanol, à raison de 30 ml/min. EXEMPLE IV : Tests in vitro et in vivo des formes galé- niques conformes à 1'invention obtenues selon les exemples I et II. a) Tenue à la température Les essais ont montré qu'à des températures com¬ prises entre -30 C et +45 °C, il n'y avait aucune modification de l'aspect ou de la structure. La forme galénique, placée sur un papier absorbant conservé à 45 °C, se ramollit très légèrement, sans laisser apparaître aucun suintement, ni tache de graisse sur le papier ; en outre, les caracté¬ ristiques physiques du noyau central lyophilisé ne sont modifiées . b) Attractivité, appétence et bioadhésion Les essais d'attractivité ont été réalisés sur deux groupes de neuf chiens (trois petits, trois moyens, trois grands) , en présentant respectivement la forme galénique selon l'exemple I (groupe A), le noyau central selon l'exemple I (groupe B) , en ayant pris soin d'introduire de la Rhodamine B uti¬ lisée comme marqueur à raison de 0,2 % (p/p) . Les résultats sont très favorables, avec une prise im¬ médiate de 100 % et 80 % respectivement pour les groupes A et B. Il faut noter que, pour le groupe B, la prise est effective pour les 20 % restants dans les dix minutes qui suivent la présentation. Les essais d'appétence et de bioadhésion sont réa¬ lisés sur les groupes A et B et un groupe C compa¬ rable, auquel est présenté un comprimé classique de composition similaire à la forme galénique selon l'exemple I. Les résultats sont très favorables à la forme galénique selon l'invention, avec une in¬ tensité moyenne de la coloration de la cavité bucco-pharyngée (échelle croissante de 0 à 4) de 4, 4 et 2 respectivement pour les groupes A, B et C. c) StabilitéThe mixture is mixed for 1 hour, then the water is removed under vacuum using microwaves (discontinuous excitation with generators of variable power between 1 and 4 KW), not exceeding 40 ° C. The granules obtained are coated in a fluidized air bed by spraying with a 5% solution of Eudragit® L 100, containing a small amount of fatty acid monoglyceride and anhydrous silicic anhydride, in a mixture 1/1 of methylene chloride and isopropanol, at a rate of 30 ml / min. EXAMPLE IV In vitro and in vivo tests of the dosage forms in accordance with the invention obtained according to Examples I and II. a) Temperature resistance Tests have shown that at temperatures between -30 ° C. and +45 ° C., there was no change in appearance or structure. The dosage form, placed on absorbent paper stored at 45 ° C, softens very slightly, without showing any oozing or grease stain on the paper; in addition, the physical characteristics of the lyophilized central core are not modified. b) Attractiveness, palatability and bioadhesion The attractiveness tests were carried out on two groups of nine dogs (three small, three medium, three large), respectively presenting the dosage form according to Example I (group A), the nucleus central according to Example I (group B), having taken care to introduce Rhodamine B used as a marker at a rate of 0.2% (w / w). The results are very favorable, with an immediate intake of 100% and 80% respectively for groups A and B. It should be noted that, for group B, the intake is effective for the remaining 20% within ten minutes which follow the presentation. The palatability and bioadhesion tests are carried out on groups A and B and a comparable group C, to which is presented a conventional tablet of composition similar to the dosage form according to Example I. The results are very favorable to the dosage form according to the invention, with an average intensity of coloring of the bucco-pharyngeal cavity (increasing scale from 0 to 4) of 4, 4 and 2 respectively for groups A, B and C. c) Stability
Les essais réalisés en b) ont été repris avec des formes identiques mais conservés six mois à 4°C. Les résultats sont tout à fait comparables . Une étude de stabilité de la forme galénique selon 1 ' exemple II a été conduite en suivant le titre de la suspension vaccinale, en fonction du temps et de la température de conservation. Cette étude a été menée en parallèle en comparaison avec un lot contrôle de suspension vaccinale, conservée sous forme liquide et conditionnée en blister. Les contrôles sont effectués dans les 7, 14 et 28 jours, 3 et 6 mois qui suivent la préparation de la suspension et de la forme galénique correspondante. On exprime la chute hebdomadaire de la dose infec¬ tieuse cyto-pathogène détruisant 50 % des cellules (DICP50) , sur les deux préparations. Les résultats sont rassemblés dans le Tableau I et montrent 1 ' intérêt particulier de la forme galénique par rapport à une présentation conventionnelle.The tests carried out in b) were repeated with identical forms but kept for six months at 4 ° C. The results are completely comparable. A stability study of the dosage form according to Example II was carried out by following the title of the vaccine suspension, as a function of the time and the temperature of storage. This study was conducted in parallel with a control batch of vaccine suspension, stored in liquid form and packaged in a blister. The controls are carried out within 7, 14 and 28 days, 3 and 6 months following the preparation of the suspension and the corresponding dosage form. The weekly drop in the infectious cyto-pathogenic dose destroying 50% of the cells (DICP50) is expressed on the two preparations. The results are collated in Table I and show the particular advantage of the dosage form compared to a conventional presentation.
TABLEAU ITABLE I
Température de stockage -80°C -20°C +4°C +25°C +35°C compositionStorage temperature -80 ° C -20 ° C + 4 ° C + 25 ° C + 35 ° C composition
SAG-2 liquide en 0 -0,025* -0,19 -0,76 -1,82 blisterSAG-2 liquid in 0 -0.025 * -0.19 -0.76 -1.82 blister
Forme galénique 0 0 -0,05 -0,1 -0,3 selon 1 ' exemple IIDosage form 0 0 -0.05 -0.1 -0.3 according to Example II
* : chute de la DICP 50 exprimée en log/semaine d) Efficacité*: drop in DICP 50 expressed in log / week d) Efficiency
Une étude a été menée avec la forme galénique selon l'exemple II en comparaison avec un appât pour chien conventionnel présentant la charge vaccinale sous forme liquide en blister. Les 14 chiens rete- nus sont divisés en 4 groupes A, B, C et D. Le groupe A (4 chiens) reçoit la forme galénique selon l'invention, le groupe B (4 chiens) reçoit le noyau central lyophilisé (sans le compartiment protec- teur) , le groupe C (4 chiens) reçoit un appât clas¬ sique, et le groupe D (2 chiens) n'est pas traité. Les chiens sont suivis pendant 30 jours, en contrô¬ lant l'évolution du taux d'anticorps antirabiques. A 30 jours, les taux de séroconversion sont supé- rieurs à 0,5 UI pour 4, 3 et 3 chiens, respective¬ ment dans les groupes A, B et C.A study was conducted with the dosage form according to Example II in comparison with a conventional dog bait having the vaccine charge in liquid form in a blister. The 14 dogs rete- naked are divided into 4 groups A, B, C and D. Group A (4 dogs) receives the dosage form according to the invention, group B (4 dogs) receives the lyophilized central nucleus (without the protective compartment) , group C (4 dogs) receives a conventional bait, and group D (2 dogs) is not treated. The dogs are followed for 30 days, by monitoring the development of the level of rabies antibodies. At 30 days, the seroconversion rates are greater than 0.5 IU for 4, 3 and 3 dogs, respectively in groups A, B and C.
Ces résultats montrent la stabilité et l'efficacité de la forme galénique selon l'invention.These results show the stability and the effectiveness of the dosage form according to the invention.
Ainsi que cela ressort de ce qui précède, 1 ' invention ne se limite nullement à ceux de ses modes de mise en oeuvre, de réalisation et d'application qui vien¬ nent d'être décrits de façon plus explicite ; elle en em¬ brasse au contraire toutes les variantes qui peuvent ve¬ nir à l'esprit du technicien en la matière, sans s'écarter du cadre, ni de la portée de la présente inven¬ tion. As is apparent from the above, the invention is in no way limited to those of its modes of implementation, embodiment and application which have just been described more explicitly; on the contrary, it embraces all the variants which can come to the mind of the technician in the matter, without departing from the framework or the scope of the present invention.

Claims

REVENDICATIONS 1) Forme galénique pour l'administration orale de substances chimiques ou médicamenteuses, du type com¬ prenant un noyau central solide contenant une ou plu- sieurs substances bioactives et une couche externe ou enrobage, caractérisée en ce que :CLAIMS 1) Galenic form for the oral administration of chemical or medicinal substances, of the type comprising a solid central core containing one or more bioactive substances and an outer layer or coating, characterized in that:
- le noyau central, hydrosoluble, et poreux com¬ prend :- the central, water-soluble, porous core includes:
. au moins une substance choisie dans le groupe qui comprend les liants sélectionnés parmi des poly¬ peptides, des polysaccharides à poids moléculaire élevé, des polymères pouvant donner des solutions colloïdales et des colloïdes, et les diluants sélectionnés parmi des polyols, des oxydes métal- liques, des carbonates, des phosphates ou la cellu¬ lose microcristalline, la quantité globale de liant et de diluant étant comprise entre 50 et 98 % en poids par rapport audit noyau central et . une quantité efficace d'au moins une substance bioactive et. at least one substance chosen from the group which comprises binders selected from poly¬ peptides, high molecular weight polysaccharides, polymers which can give colloidal solutions and colloids, and diluents selected from polyols, metal oxides , carbonates, phosphates or microcrystalline cellu¬ lose, the overall amount of binder and diluent being between 50 and 98% by weight relative to said central core and. an effective amount of at least one bioactive substance and
- la couche externe, à caractère hydrophobe et ap- pétant, comprend : au moins une substance lipidique choisie parmi les alcools gras, les acides gras, les esters de glycerol, les huiles hydrogénées, les cires, la paraffine, la lanoline, l'huile de coprah et les sels d'acides gras ; un agent de modulation du délitement et de l'adhésion de ladite couche externe, soluble ou dispersible dans la masse lipidique, choisi parmi des polymères sélectionnés dans le groupe qui comprend des résines acryliques, des acétates de polyvinyle, des résines de polyalkylène, des co- polymères éthylène/acétate de vinyle (EVA) , les polymères réticulés d'amidon, de dextran, d'inuline ou de vinylpyrrolidone et des dérivés cellulosiques sélectionnés parmi 1 'hydroxypropylcellulose, 1 'hydroxypropylméthylcellulose, 1 ' éthylcellulose, la carboxyméthylcellulose ; etthe outer layer, hydrophobic and appetizing, comprises: at least one lipid substance chosen from fatty alcohols, fatty acids, glycerol esters, hydrogenated oils, waxes, paraffin, lanolin, coconut oil and fatty acid salts; an agent for modulating the disintegration and the adhesion of said outer layer, soluble or dispersible in the lipid mass, chosen from polymers selected from the group which comprises acrylic resins, polyvinyl acetates, polyalkylene resins, co - ethylene / vinyl acetate polymers (EVA), cross-linked polymers of starch, dextran, inulin or vinylpyrrolidone and cellulose derivatives selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, carboxymethylcellulose; and
. des substances appétentes, naturelles ou synthé- tiques.. palatable, natural or synthetic substances.
2) Forme galénique selon la revendication 1, caractérisée en ce que le noyau central comprend en outre un ou plusieurs additifs choisis parmi des substances modifiant ou masquant le goût, des agents modulant le délitement, des promoteurs d'absorption, des agents de surface choisis parmi des tensio-actifs non ioniques ou cationiques, des agents colorants et des agents conserva¬ teurs .2) Dosage form according to claim 1, characterized in that the central core further comprises one or more additives chosen from substances modifying or masking the taste, agents modulating the disintegration, absorption promoters, selected surfactants among nonionic or cationic surfactants, coloring agents and preserving agents.
3) Forme galénique selon la revendication 1 ou la revendication 2, caractérisée en ce que la couche externe comprend en outre des substances minérales choi¬ sies dans le groupe qui comprend des oxydes minéraux, des phosphates, des carbonates, les argiles et le talc et/ou un agent tensio-actif choisi parmi les esters de sorbi- toi, les polysorbates de polyoxyethylene, les lécithines et les esters de sorbitane.3) Galenic form according to claim 1 or claim 2, characterized in that the outer layer further comprises mineral substances selected from the group which comprises mineral oxides, phosphates, carbonates, clays and talc and / or a surfactant chosen from sorbite esters, polyoxyethylene polysorbates, lecithins and sorbitan esters.
4) Forme galénique selon l'une quelconque des revendications 1 à 3 , caractérisée en ce que les diluants et liants du noyau interne sont sélectionnés parmi la gomme arabique, la gomme xanthane, la pectine, les poly¬ ols du type sorbitol, xylitol, mannitol et leurs mélanges .4) Galenic form according to any one of claims 1 to 3, characterized in that the diluents and binders of the internal core are selected from gum arabic, xanthan gum, pectin, polyols of the sorbitol, xylitol type, mannitol and mixtures thereof.
5) Forme galénique selon l'une quelconque des revendications 1 à 4, caractérisée en ce que la substance lipidique de ladite couche externe est choisie parmi la paraffine, l'huile de coprah, l'acide palmitique et les esters du glycerol et en ce que l'agent de modulation du délitement de ladite couche externe est choisi parmi les copolymères éthylène/acétate de vinyle et les polysaccharides réticulés. 6) Forme galénique selon l'une quelconque des revendications 1 à 5, caractérisée en ce que les sub¬ stances bioactives du noyau interne sont choisies parmi les vaccins, les cytokines, les anti-cancéreux, les fac- teurs de croissance, les adjuvants de l'immunité, les facteurs support de transgénie, les facteurs d'attachement ou d'anti-attachement locaux.5) Galenic form according to any one of claims 1 to 4, characterized in that the lipid substance of said outer layer is chosen from paraffin, coconut oil, palmitic acid and glycerol esters and in that that the agent for modulating the disintegration of said outer layer is chosen from ethylene / vinyl acetate copolymers and crosslinked polysaccharides. 6) Galenic form according to any one of claims 1 to 5, characterized in that the bioactive substances of the internal nucleus are chosen from vaccines, cytokines, anti-cancer agents, growth factors, adjuvants immunity, transgenic support factors, local attachment or anti-attachment factors.
7) Forme galénique selon la revendication 6, caractérisée en ce que le noyau interne comprend en tant que substance bioactive, un vaccin choisi parmi les vac¬ cins anti-viraux, les vaccins anti-parasitaires, les vac¬ cins anti-bactériens, les vaccins contraceptifs.7) Galenic form according to claim 6, characterized in that the internal nucleus comprises, as bioactive substance, a vaccine chosen from anti-viral vac¬ cins, anti-parasitic vaccines, anti-bacterial vac¬ cins, contraceptive vaccines.
8) Forme galénique selon la revendication 6 ou la revendication 7, caractérisée en ce que le noyau in- terne comprend en tant que substance bioactive, une sus¬ pension vaccinale antirabique de souche SAG-2.8) Galenic form according to claim 6 or claim 7, characterized in that the internal nucleus comprises, as bioactive substance, an anti-rabies vaccine sus¬ pension of strain SAG-2.
9) Forme galénique selon l'une quelconque des revendications 1 à 8, caractérisée en ce qu'elle présente la formule suivante : - noyau central : diluants et/ou liants 50 à 98 % substances bioactives 0,25 à 50 % autres additifs 0 à 1,75 %9) Dosage form according to any one of claims 1 to 8, characterized in that it has the following formula: - central core: diluents and / or binders 50 to 98% bioactive substances 0.25 to 50% other additives 0 1.75%
- couche externe : substances lipidiques 40 à 93 % polymères 4 à 30 % substances appétentes et autres additifs 3 à 30 %- outer layer: lipid substances 40 to 93% polymers 4 to 30% palatable substances and other additives 3 to 30%
10) Procédé de préparation d'une forme galé- nique selon l'une quelconque des revendications 1 à 9, caractérisé en ce que l'on effectue les opérations sui¬ vantes : a) préparation d'une pâte contenant les diffé¬ rents constituants du noyau central, à savoir, substances bioactives, diluants, liants et éventuellement un ou plu¬ sieurs additifs et une quantité d'eau convenable pour régler l'homogénéité et la viscosité de la suspension obtenue, b) solidification du produit obtenu en a) , c) enrobage des produits obtenus en b) , avec un mélange en solution ou en suspension, comprenant au moins une substance lipidique, un agent de modulation du délitement de la couche externe et une substance appé- tente.10) Process for the preparation of a galenical form according to any one of claims 1 to 9, characterized in that the following operations are carried out: a) preparation of a paste containing the different constituents of the central core, namely, bioactive substances, diluents, binders and possibly one or more additives and an amount of water suitable for adjust the homogeneity and the viscosity of the suspension obtained, b) solidification of the product obtained in a), c) coating of the products obtained in b), with a mixture in solution or in suspension, comprising at least one lipid substance, one agent modulation of the disintegration of the outer layer and an appetizing substance.
11) Procédé de préparation selon la revendica- tion 10, caractérisé en ce que ladite solidification est réalisée par une opération physique telle qu' evaporation, dessiccation ou lyophilisation.11) Preparation process according to claim 10, characterized in that said solidification is carried out by a physical operation such as evaporation, drying or lyophilization.
12) Procédé de préparation selon la revendica¬ tion 10 ou la revendication 11, caractérisé en ce que lorsque la solidification est réalisée par lyophi¬ lisation, l'opération est conduite en deux temps :12) Preparation process according to claim 10 or claim 11, characterized in that when the solidification is carried out by freeze-drying, the operation is carried out in two stages:
(i) division de la pâte en quantités unitaires de forme et de volume prédéterminés, et(i) dividing the dough into unit quantities of predetermined shape and volume, and
(ii) lyophilisation, étant entendu que les étapes (i) et (ii) peuvent être réalisées indifféremment dans n'importe quel ordre.(ii) lyophilization, it being understood that steps (i) and (ii) can be carried out in any order.
13) Procédé de préparation selon la revendica¬ tion 10 ou la revendication 11, caractérisé en ce que lorsque la solidification est réalisée par evaporation, l'opération est conduite dans un mélangeur sécheur, sous pression réduite et exposition intermittente aux hyper- fréquences.13) Preparation process according to claim 10 or claim 11, characterized in that when the solidification is carried out by evaporation, the operation is carried out in a drying mixer, under reduced pressure and intermittent exposure to microwave frequencies.
14) Médicament, caractérisé en ce qu'il est constitué par une forme galénique selon l'une quelconque des revendications 1 à 9.14) Medicament, characterized in that it is constituted by a galenical form according to any one of claims 1 to 9.
15) Vecteur immunologique, caractérisé en ce qu'il est constitué par une forme galénique selon l'une quelconque des revendications 1 à 9.15) Immunological vector, characterized in that it consists of a galenical form according to any one of claims 1 to 9.
16) Produit diététique, caractérisé en ce qu'il comprend une forme galénique selon l'une quelconque des revendications 1 à 5. 17) Produit alimentaire, caractérisé en ce qu'il comprend une forme galénique selon l'une quelconque des revendications 1 à 5. 16) Dietetic product, characterized in that it comprises a pharmaceutical form according to any one of claims 1 to 5. 17) Food product, characterized in that it comprises a dosage form according to any one of claims 1 to 5.
EP95900166A 1993-10-29 1994-10-27 Orally-administered dosage form for animals, preparation method therefor and uses thereof Expired - Lifetime EP0725627B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9312954 1993-10-29
FR9312954A FR2711525B1 (en) 1993-10-29 1993-10-29 Galenic form for oral administration for animals, its preparation process and its applications.
PCT/FR1994/001251 WO1995011665A1 (en) 1993-10-29 1994-10-27 Orally-administered dosage form for animals, preparation method therefor and uses thereof

Publications (2)

Publication Number Publication Date
EP0725627A1 true EP0725627A1 (en) 1996-08-14
EP0725627B1 EP0725627B1 (en) 1999-06-23

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US (1) US5683722A (en)
EP (1) EP0725627B1 (en)
JP (1) JPH09505564A (en)
AT (1) ATE181500T1 (en)
AU (1) AU688408B2 (en)
CA (1) CA2175077A1 (en)
DE (2) DE69419260T2 (en)
ES (1) ES2095819T1 (en)
FR (1) FR2711525B1 (en)
NZ (1) NZ275837A (en)
WO (1) WO1995011665A1 (en)

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WO2013037650A1 (en) 2011-09-15 2013-03-21 Friulchem Spa Compositions for oral administration to animals, production methods thereof and uses of same
WO2014033230A1 (en) 2012-08-31 2014-03-06 Friulchem Spa Compositions for oral administration to animals, production methods thereof and uses of same

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WO2013037650A1 (en) 2011-09-15 2013-03-21 Friulchem Spa Compositions for oral administration to animals, production methods thereof and uses of same
US11103524B2 (en) 2011-09-15 2021-08-31 Friulchem Spa Compositions for oral administration to animals, processes for obtaining the same and the uses thereof
WO2014033230A1 (en) 2012-08-31 2014-03-06 Friulchem Spa Compositions for oral administration to animals, production methods thereof and uses of same

Also Published As

Publication number Publication date
ES2095819T1 (en) 1997-03-01
DE69419260D1 (en) 1999-07-29
CA2175077A1 (en) 1995-05-04
JPH09505564A (en) 1997-06-03
ATE181500T1 (en) 1999-07-15
FR2711525A1 (en) 1995-05-05
NZ275837A (en) 1997-11-24
AU688408B2 (en) 1998-03-12
DE725627T1 (en) 1997-04-30
FR2711525B1 (en) 1996-01-12
EP0725627B1 (en) 1999-06-23
AU8109294A (en) 1995-05-22
US5683722A (en) 1997-11-04
WO1995011665A1 (en) 1995-05-04
DE69419260T2 (en) 1999-12-02

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